The inability of cells to maintain genomic integrity leads to the rapid accumulation of DNA mutations, a scenario that underlies many diseases. In particular, the ablation of DNA mismatch repair (MMR) activity has been linked to several forms of cancer, microsatellite instability, and most notably chemotherapeutic drug resistance. DNA damaging agents used as drug treatments are often associated with a resistance phenotype in cells with decreased MMR activity. Many of the most commonly used antimalarial drugs are DNA altering agents and may play a critical role in the selection of a drug resistant phenotype within the malaria parasite. This resistance may be directly associated with a loss or decrease of MMR activity within parasites. Given Plasmodium falciparum's rapid development of drug resistance and its unusually high A-T rich genome, characteristic of a mutator phenotype, it is not difficult to imagine that the parasite has greatly diminished post-replication repair efficiency. Moreover, the absence of an MSH3 and MSH5 homologue from the Plasmodium genome may allow the persistence of certain types of DNA lesions that would otherwise be removed by the MMR pathway. It is our hypothesis that P. falciparum drug resistant strains have decreased repair of mispaired DNA substrates and that this decreased activity is the underlying mechanism in the development of malaria drug resistance. Efficient MMR plays an indispensable role in determining cellular sensitivity to DNA altering agents. We further hypothesize that current antimalarial drugs, some of which are known DNA altering agents, are selecting for a population of parasites possessing a decreased MMR efficiency. Therefore, we propose to investigate the role that MMR plays in Plasmodium falciparum drug resistance. PUBLIC HEALTH RELEVANCE Human malaria is an enormous global health problem, infecting 300-500 million people, and causing 1-3 million deaths annually. Understanding how Plasmodium falciparum maintains genomic integrity is uncharted territory within malaria biology and may be the key to elucidating the parasites extraordinary adaptability to chemotherapy. It is our hypothesis that P. falciparum drug resistant strains have decreased repair of mispaired DNA substrates and that this decreased activity is the underlying mechanism in the development of malaria drug resistance.